Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice

Area of Science:

• Nephrology
• Cardiovascular Research
• Metabolic Science

Background:

• Cardiovascular events are the primary cause of mortality in chronic kidney disease (CKD) patients.
• CKD is associated with impaired renal cholesterol and vitamin D metabolism.
• This study investigates the impact of induced nephropathy on these metabolic pathways and atherosclerosis.

Purpose of the Study:

• To investigate the role of renal cholesterol and vitamin D metabolism in CKD.
• To determine the effect of adenine-induced nephropathy on atherosclerotic phenotype in Apolipoprotein E knockout mice.
• To compare the atherosclerotic phenotype in mice with normal renal function versus those with induced nephropathy.

Main Methods:

• Adenine was administered to Apolipoprotein E knockout mice fed a western diet to induce nephropathy.
• Renal function, fecal output, atherosclerosis, serum lipoprotein composition, hepatic lipids, and gene expression were assessed.
• Bone microarchitecture was analyzed using microcomputed tomography (microCT).

Main Results:

• Adenine-induced nephropathy led to altered urinary excretion of sodium, calcium, and phosphate, and reduced urinary pH.
• Mice with induced nephropathy exhibited reduced atherosclerosis, increased cholesterol efflux, and increased fecal excretion of cholesteryl ester and triglycerides.
• Key genes involved in lipid metabolism (e.g., Cyp27a1, Cyp7a1, Scarb1) were upregulated in the liver, while genes related to vitamin D and sodium homeostasis (e.g., Vdr, Slc9a3) were downregulated in the kidneys.

Conclusions:

• Adenine-induced tubular damage resulted in an athero-protective effect.
• This atheroprotection was attributed to enhanced cholesterol efflux and increased fecal lipid elimination.
• Bone growth was negatively affected, indicating broader metabolic consequences of adenine-induced nephropathy.